Systems, methods and devices for peripheral neuromodulation for treating diseases related to overactive bladder

ABSTRACT

In some embodiments, systems and methods can include a wearable device with an electrically conductive skin interface that excites the underlying nerves from a transcutaneous surface stimulator. The device may be sized for a range of user sizes with stimulation electrodes positioned to target the appropriate nerves, such as the saphenous and/or posterior tibial nerves. Transcutaneous afferent stimulation of one, two, or more peripheral nerves can modulate a brain or spinal pathway associated with bladder function.

INCORPORATION BY REFERENCE

This application is the U.S. National Stage under 37 C.F.R. § 371 of PCTApp. No. PCT/US2017/014431, which in turn is a nonprovisionalapplication that claims the benefit under 35 U.S.C. § 119(e) of U.S.Prov. App. No. 62/281,606 filed on Jan. 21, 2016, U.S. Prov. App. No.62/352,462 filed on Jun. 20, 2016, and U.S. Prov. App. No. 62/365,326filed on Jul. 21, 2016, each of which are hereby incorporated byreference in their entireties. Any and all applications for which aforeign or domestic priority claim is identified in the Application DataSheet as filed with the present application are hereby incorporated byreference under 37 CFR 1.57.

BACKGROUND Field of the Invention

The invention relates in some aspects to systems and methods fortreating overactive bladder and related conditions.

Description of the Related Art

Overactive bladder (OAB) is a common condition affecting men and womenwith an estimated prevalence at 16% of the population affecting up to anestimated 500 million people by 2018. The total annual cost burden ofOAB is projected to be US$3.9 billion across six countries (Canada,Germany, Italy, Spain, Sweden and the UK). Symptoms of overactivebladder include the uncontrollable desire to urinate immediately, knownas urgency, which may or may not be followed by the loss of urine(incontinence), increased frequency of urination, and/or nocturia.Nocturia is a medical condition that results in the need to wake up one,two, three, or more times during the night to urinate. Lower urinarytract (LUT) dysfunction may be secondary to a variety of non-neurologicor neurologic causes, including stroke, spinal cord injury, multiplesclerosis or neurodegenerative conditions such as Parkinson's disease.Standard medical treatment options for overactive bladder includebehavioral strategies such as timed voiding or pelvic muscle exercises,or pharmacologic therapies such as antimuscarinic medications orbotulinum toxin injections into the bladder. However, oral medicationscan be incompletely effective and carry a high risk of adverse sideeffects leading to intolerance and frequent discontinuation. Efficacioustherapies with reduced side effects are needed.

SUMMARY

In some embodiments, disclosed herein is a method of treating urinarysymptoms in a patient with dual transcutaneous stimulation of asaphenous nerve and a posterior tibial nerve. The method can include, insome embodiments, any number of the following: positioning a firstperipheral nerve effector on the patient's skin to stimulate thesaphenous nerve of the patient; positioning a second peripheral nerveeffector on the patient's skin to stimulate the posterior tibial nerveof the patient; delivering a first electrical nerve stimulation signaltranscutaneously to the saphenous nerve through the first peripheralnerve effector; delivering a second electrical nerve stimulation signaltranscutaneously to the posterior tibial nerve through the secondperipheral nerve effector; receiving an input relating to autonomicnervous system activity of the patient; and modifying at least one brainor spinal cord autonomic feedback loop relating to bladder functionbased on the input to balance parasympathetic and sympathetic nervoussystem activity of the patient. In some embodiments, the method does notutilize any implantable components, and only involves transcutaneousstimulation. The first peripheral nerve effector and the secondperipheral nerve effector can be both positioned proximate the knee ofthe patient. The first electrical stimulation signal can be differentfrom the second electrical stimulation signal. The first electricalstimulation signal can have a first frequency different from a secondfrequency of the second electrical stimulation signal. The firstelectrical stimulation signal can have an amplitude different from thesecond electrical stimulation signal. The first or second frequency canbe, for example, from about 10 Hz to about 20 Hz. The first or secondfrequency can be, for example, from about 5 Hz to about 30 Hz. Receivingan input relating to autonomic nervous system activity of the patientcan include any number of the following: receiving data from a sensorthat measures autonomic nervous system activity of the patient;receiving data from a sensor that measures heart rate variability of thepatient; receiving heart rate variability data from an optical sensormeasuring blood flow characteristics and disposed proximate a vesselproximate a knee of the patient; receiving data from a sensor thatmeasures galvanic skin response of the patient; receiving data relatingto urinary symptoms of the patient; and/or receiving data relating tonocturia episodes of the patient.

Also disclosed herein is a wearable device for dual transcutaneousstimulation of the saphenous nerve and posterior tibial nerve and fortreating urinary symptoms in a patient. The device can include, in someembodiments, any number of the following features: a controller; a firstperipheral nerve effector, comprising at least one stimulation electrodeconfigured to be positioned to transcutaneously modulate the saphenousnerve; a second peripheral nerve effector, comprising at least onestimulation electrode configured to be positioned to transcutaneouslymodulate the posterior tibial nerve; and at least one biomedical sensoror data input source configured to provide feedback information. Thecontroller can include a processor and a memory for receiving thefeedback information from the sensor that, when executed by theprocessor, cause the device to adjust one or more parameters of a firstelectrical stimulus and a second electrical stimulus based at least inpart on the feedback information; and/or deliver the first electricalstimulus to the saphenous nerve through the first peripheral nerveeffector and deliver the second electrical stimulus to the posteriortibial nerve through the second peripheral nerve effector to reduceurinary symptoms by modifying a brain or spinal cord autonomic feedbackloop relating to bladder function and balancing sympathetic nerve andparasympathetic nerve activity. In some embodiments, the device is notconfigured for implantation within the patient. The feedback informationcan include real-time feedback information. The first electricalstimulus can have a frequency of, for example, between about 10 Hz andabout 20 Hz. The second electrical stimulus can have a frequency of, forexample, between about 5 Hz and about 30 Hz. The feedback informationcan include autonomic nervous system activity of the patient. Thefeedback information can include heart rate variability. The feedbackinformation can also include information relating to nocturia events ofthe patient. The feedback information can also include informationrelating to patient sleep state.

In some embodiments, disclosed herein is a method of treating urinarysymptoms in a patient. The method can include any number of thefollowing: positioning a first electrode at a first location on a skinsurface relative to a first afferent peripheral nerve; positioning asecond electrode at a second location on the skin surface relative to asecond afferent peripheral nerve; positioning a third electrode at athird location on the skin surface spaced apart from the first electrodeand the second electrode; delivering a first stimulus to the firstperipheral nerve through the first electrode; and delivering a secondstimulus to the second peripheral nerve through the second electrode. Insome embodiments, the third electrode is a single common returnelectrode to the first electrode and the second electrode. In someembodiments, the first electrode, second electrode, and third electrodeare positioned such that electric fields between the first electrode andthe third electrode pass through the first afferent peripheral nerve,and electric fields between the second electrode and the third electrodepass through the second afferent peripheral nerve. The first stimulusand the second stimulus can modify at least one brain or spinal cordautonomic feedback loop relating to bladder function. In someembodiments, the first afferent peripheral nerve comprises the posteriortibial nerve. In some embodiments, the second afferent peripheral nervecomprises the saphenous nerve. The symptoms can include, for example,overactive bladder, nocturia, urinary urgency, and/or urinary frequency.In some embodiments, the first electrode, second electrode, and thirdelectrode are all connected on a wearable device and positioned on thecalf proximate to, and distal to the patient's knee, ankle, and/or foot.

In some embodiments, disclosed herein is a method of treating urinarysymptoms in a patient. The method can include any number of thefollowing: positioning a first pair of electrodes comprising an anodeand a cathode at a first location on a skin surface relative to a firstperipheral nerve; positioning a second pair of electrodes comprising ananode and a cathode at a second location on the skin surface relative toa second peripheral nerve; delivering a first stimulus to the firstperipheral nerve through the first pair of electrodes; and delivering asecond stimulus to the second peripheral nerve through the second pairof electrodes. In some embodiments, the first pair of electrodes andsecond pair of electrodes are positioned such that electric fieldsbetween the first pair of electrodes pass through the first peripheralnerve, and electric fields between the second pair of electrodes passthrough the second peripheral nerve. The first stimulus and the secondstimulus can modify at least one brain or spinal cord autonomic feedbackloop relating to bladder function.

Also disclosed herein is a system of treating urinary symptoms in apatient, that can include in some embodiments any number of thefollowing: a wearable housing configured to be positioned on a patient'scalf proximate the knee of the patient; a first electrode configured tobe positioned at a first location on a skin surface relative to a firstafferent peripheral nerve; a second electrode configured to bepositioned at a second location on the skin surface relative to a secondafferent peripheral nerve; a third electrode configured to be positionedat a third location on the skin surface spaced apart from the firstelectrode and the second electrode; a controller configured to deliver afirst stimulus to the first peripheral nerve through the firstelectrode; and a second stimulus to the second peripheral nerve throughthe second electrode to modify at least one brain or spinal cordautonomic feedback loop relating to bladder function. The thirdelectrode can be a single common return electrode to the first electrodeand the second electrode. The first electrode, second electrode, andthird electrode can be configured to be positioned such that electricfields between the first electrode and the third electrode pass throughthe first afferent peripheral nerve, and electric fields between thesecond electrode and the third electrode pass through the secondafferent peripheral nerve. The wearable housing can be attached to eachof the first electrode, the second electrode, and the third electrode.In some embodiments, the first afferent peripheral nerve is theposterior tibial nerve, and the second afferent peripheral nerve is thesaphenous nerve.

Also disclosed herein is a system of treating urinary symptoms in apatient, the system including any number of the following: a first pairof electrodes comprising an anode and a cathode and configured to bepositioned at a first location on a skin surface relative to a firstafferent peripheral nerve; a second pair of electrodes comprising ananode and a cathode and configured to be positioned at a second locationon the skin surface relative to a second afferent peripheral nerve; acontroller configured to deliver a first stimulus to the firstperipheral nerve through the first pair of electrodes; and a secondstimulus to the second peripheral nerve through the pair of secondelectrodes to modify at least one brain or spinal cord autonomicfeedback loop relating to bladder function. The first pair of electrodesand second pair of electrodes can be configured to be positioned suchthat electric fields between the first pair of electrodes pass throughthe first peripheral nerve, and electric fields between the second pairof electrodes pass through the second peripheral nerve.

In some embodiments, disclosed herein is a wearable device for treatingurinary symptoms in a patient. The device can include any number of thefollowing: a controller;

a first peripheral nerve effector, comprising at least one stimulationelectrode configured to be positioned to transcutaneously modulate afirst afferent nerve pathway associated with bladder function; and asecond peripheral nerve effector, comprising at least one stimulationelectrode configured to be positioned to transcutaneously modulate asecond afferent nerve pathway associated with bladder function; and atleast one input source configured to provide feedback information. Thecontroller can include a processor and a memory for receiving thereal-time feedback information from the input source that, when executedby the processor, cause the device to adjust one or more parameters of afirst electrical stimulus based at least in part on the feedbackinformation; adjust one or more parameters of a second electricalstimulus based at least in part on the feedback information independentfrom the first electrical stimulus; deliver the first electricalstimulus to a first afferent nerve pathway through the first peripheralnerve effector to reduce urinary symptoms by modifying a first brain orspinal cord autonomic feedback loop relating to bladder function; anddeliver the second electrical stimulus to a second afferent nervepathway through the second peripheral nerve effector to reduce urinarysymptoms by modifying a second brain or spinal cord autonomic feedbackloop relating to bladder function. Adjusting the one or more parametersof the first electrical stimulus and the second electrical stimulus cancontribute to balancing sympathetic and parasympathetic nervous systemactivity.

In some embodiments, systems and methods can include a wearable devicewith an electrically conductive skin interface that excite theunderlying nerves from a transcutaneous surface stimulator. The devicemay be sized for a range of user sizes with stimulation electrodespositioned to target the appropriate nerves, as in the device describedin, for example, U.S. Pat. No. 9,452,287 to Rosenbluth et al., PCT Pub.No. WO 2015/187712 to Wong et al., and PCT App. No. PCT/US2016/037080,each of which is incorporated by reference in their entireties.

This invention describes, in some embodiments, a wearable system thatuses transcutaneous sensory stimulation in order to improve symptoms ofoveractive bladder and urinary incontinence. In some embodiments, keyfactors of this system enable chronic, home-use to improve the efficacyof peripheral nerve stimulation by avoiding the inconvenience offrequent office visits and invasive aspects of using percutaneous tibialneuromodulation or sacral nerve stimulation. Some embodiments canadvantageously utilize transcutaneous neuromodulation of peripheralafferent nerve pathways to non-invasively affect brain or spinal cordpathways associated with physiologic, such as bladder function.

Chronic peripheral nerve stimulation in a wearable form that can beintegrated easily into an individual's life, allowing full mobility andease of use, can improve the efficacy of urinary neuromodulation.However, home use of a percutaneous system can be inconvenient andtechnically difficult for the patient. Transcutaneous neuromodulation isa more suitable modality for home use but is currently limited by theform factor depending on the needs for chronic daily use. Furthermore,adding aspects of responsiveness and more frequent use could greatlyimprove the effectiveness and comfort of such a chronic use device.

The effects of peripheral nerve stimulation on bladder function mayoccur only during the period of active stimulation or may outlast thestimulation period after stimulation has ceased. Different mechanismssuch as the modulation of urinary reflexes or induction of brain orspinal plasticity can be responsible for these experimental and clinicalobservations. Furthermore, the onset of the effects of stimulation mayoccur acutely (e.g., during or immediately following therapy) or onlyafter several stimulation sessions in a chronic manner. For example, theeffect of transcutaneous tibial and/or saphenous nerve stimulation onpatient related outcomes is estimated at 4-6 weeks after the initiationof weekly stimulation sessions. Depending on the underlying mechanismsand the time course of beneficial effects, stimulation may requiredelivery in a continuous fashion such as in sacral nerve stimulation, indiscrete scheduled sessions or in an on-demand, conditional manner.Conditional stimulation may either rely on patient control to identifythe sense of urinary urge or automated detection of an involuntarydetrusor contraction (IDC) which is responsible for urgency symptoms orevolution to frank incontinence.

Several peripheral nerves can be selected as targets for urinaryneuromodulation, including the tibial, pudendal, and dorsal genitalnerve, with demonstrated acute and chronic effects on bladder functionin animal and human experimental studies. The saphenous nerve canacutely reduce bladder hyperexcitability. The saphenous nerve is apurely sensory nerve that innervates the skin on the medial lower leg.Its proximity to the skin surface makes it an advantageous target fortranscutaneous stimulation. Selective stimulation of the tibial andsaphenous nerve can reduce symptoms of overactive bladder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates non-limiting structures and pathways associated withbladder function.

FIGS. 1A and 1B illustrate examples of stimulation waveforms, accordingto some embodiments of the invention.

FIG. 2 schematically illustrates a flow chart incorporating astimulation protocol, according to some embodiments of the invention.

FIG. 3 illustrates a calf band stimulator configured to be positionedproximate the knee, according to some embodiments of the invention.

FIGS. 4A-4B illustrate ankle stimulators, according to some embodimentsof the invention.

FIGS. 5A-5C illustrate non-limiting embodiments of potential electrodeplacement locations for nerve stimulation.

FIGS. 6-7 illustrate views of stimulation devices with stickyelectrodes, according to some embodiments of the invention.

FIG. 8 illustrates a thin, bandage-like electrode that can be attachedto the patient, according to some embodiments of the invention.

FIG. 9 illustrates an embodiment of a distal saphenous nerve sensingand/or stimulation technique.

FIG. 10 illustrates a stimulation device including a housing, accordingto some embodiments of the invention.

FIG. 10A illustrates an embodiment of an electrode array with elementsthat can be individually addressable.

FIG. 10B illustrates an embodiment of a stimulation system including awearable device on the ankle or other desired anatomical location, aswell as an implanted stimulation electrode around a target nerve.

FIGS. 11A-11E and 12A illustrate that systems and methods of peripheralnerve stimulation can be provided that target one, two, or moreindividual nerves.

FIGS. 12 and 13 show that the electrodes can be disposed on a wearableband (or sleeve) that can be circumferential or non-circumferential, andworn around the ankle, knee, leg, or other body part according to someembodiments of the invention.

FIGS. 14 and 15 illustrate embodiments of stimulation systems with atleast three electrodes that can be configured to independently stimulatea plurality of nerves.

FIGS. 16A-16C illustrate clinical data relating to saphenous nervestimulation, according to some embodiments of the invention.

FIGS. 17A-17F illustrate clinical data relating to tibial nervestimulation, according to some embodiments of the invention.

DETAILED DESCRIPTION

As used herein, the terms “stimulating” and “stimulator” generally referto delivery of a signal, stimulus, or impulse to neural tissue of thetargeted region. The effect of such stimulation on neuronal activity istermed “modulation;” however, for simplicity, the terms “stimulating”and “modulating,” and variants thereof, are sometimes usedinterchangeably herein. The effect of delivery of the signal to theneural tissue may be excitatory or inhibitory and may potentiate acuteand/or long-term changes in neuronal activity. For example, the effectof “stimulating” or “modulating” a neural tissue may comprise one ormore of the following effects: (a) depolarizing the neurons such thatthe neurons fire action potentials, (b) hyperpolarizing the neurons toinhibit action potentials, (c) depleting neurons ion stores to inhibitfiring action potentials (d) altering with proprioceptive input, (e)influencing muscle contractions, (f) affecting changes inneurotransmitter release or uptake, or (g) inhibiting firing.“Proprioception” refers to one's sensation of the relative position ofone's own body parts or the effort being employed to move one's bodypart. Proprioception may otherwise be referred to as somatosensory,kinesthetic or haptic sensation. A “proprioceptor” is a receptorproviding proprioceptive information to the nervous system and includesstretch receptors in muscles, joints, ligaments, and tendons as well asreceptors for pressure, temperature, light and sound. An “effector” isthe mechanism by which the device modulates the target nerve. Forexample, the “effector” may be electrical stimulation of the nerve ormechanical stimulation of proprioceptors.

“Electrical stimulation” refers to the application of electrical signalsto the soft-tissue and nerves of the targeted area. The “cloud” refersto a network of computers communication using real-time protocols suchas the internet to analyze, display and interact with data acrossdistributed devices.

Some forms of therapy for control of urinary symptoms include electricalneuromodulation, including transcutaneous and/or percutaneous peripheralnerve stimulation and/or implantable pudendal or sacral nervestimulation. Neuromodulation of the urinary system can be highlyeffective in the control of lower urinary tract symptoms. Modulation ofurinary reflexes can be accomplished in some embodiments by stimulationof lumbosacral afferent pathways. Sacral neuromodulation can includesurgical placement of an implant at the level of the S3 sacral foraminaand can be highly effective and durable but requires an invasiveprocedure. The stimulation can be performed continuously and in anopen-loop. Sacral stimulation can lead to modulation of the micturitionreflex at the spinal or supraspinal level. Although sacral nervestimulation is considered relatively long-lasting, it is invasive andside effects include buttock, lower extremity or pelvic pain, lead siteinfection, and negative changes in urinary, bowel or sexual function.Device related complications include battery failure, lead migration, orloss of efficacy necessitating revision or explantation of the device.

Modulation of bladder dysfunction can also be achieved in some casesusing intermittent tibial nerve stimulation. The acute effects ofstimulation can include improvements in cystometry measures, includingbladder capacity. Stimulation can be performed, for example, weekly witha percutaneous needle electrode in 30 minute sessions. As thestimulation is not continuous, there can be a carry-over effect. Theeffects of percutaneous tibial nerve stimulation can be maintainedafter, for example, 12 weeks, but a continued schedule of sessions canbe required thereafter every month to maintain efficacy. Stimulation ofthe posterior tibial nerve can lead to spinal root L4-S3 stimulationinhibiting bladder activity although it is unclear whether spinal reflexor brain networks are responsible for the effects. The presence of acarry-over effect after the period of stimulation suggests a plasticitymechanism either at the level of the spine or brain.

Transcutaneous stimulation of one, two, or more target nerves ofinterest, e.g., the saphenous nerve, and/or or tibial nerve stimulationcan control urinary incontinence symptoms with varying levels ofsuccess. However, in some embodiments, transcutaneous stimulation can bepreferred. The feasibility of home-based stimulation has been limited bydevice form factor and limited programming flexibility of currentdevices.

In some embodiments, more continuous stimulation at the level of thetibial and/or saphenous nerve can potentially improve the efficacy ofperipheral nerve stimulation for conditions such as, for example,urinary incontinence. An implanted percutaneous tibial nerve stimulatorcan be efficacious and safe. Some embodiments can use frequencies of,for example, between about 1 kHz and about 100 kHz, 1 Hz and about 100Hz, between about 1 Hz and about 50 Hz, between about 5 Hz and about 30Hz, or between about 10 Hz and about 20 Hz stimulation for a specifiedperiod of time, such as about, at least about, or no more than about 20,30, 40, 50 or 60 minutes at a sensory or sub-sensory threshold or belowmotor contraction threshold that is tolerable to the patient. Varyingthe regularity of stimulation and the frequency of the stimulationwaveform may improve tolerance or efficacy in some cases. An increasedfrequency of stimulation may be more effective but could require a morechronic at-home portable system to provide continuous transcutaneousstimulation throughout the day.

Stimulating at intensities below the sensory threshold or with highfrequencies (e.g., between about 1 kHz to about 100 kHz) can avoid thediscomfort (tingling, numbness, pain) that can be associated withperipheral nerve stimulation. Because the exact electrode position, sizeand surface contact have a large effect on the stimulation level and theanatomical structures that receive the stimulation, the sensorythreshold may need to be calibrated for each patient and even for eachsession. This calibration may be done by the user manually setting thestimulation parameters or otherwise indicating their sensory threshold.Another possible embodiment is for the device to automatically sweepthrough a range of stimulation parameters and the patient chooses themost comfortable set of parameter values. Another possible embodiment isfor the patient to choose from among a set of previously chosenparameter values that provided effective and comfortable stimulation.

In some embodiments, disclosed herein are peripheral nerve stimulatorsto improve conditions including but not limited to urinary dysfunction.The stimulation can target one, two, three, or more nerves associatedwith bladder function. The nerves can include, for example, the tibialnerve or posterior tibial nerve, which can branch into the medial andlateral plantar nerve branches, and the calcaneal nerves. The saphenousnerve is the cutaneous branch of the femoral nerve. Other nervesinclude, for example, the pudendal nerve, pelvic nerve, dorsal genitalnerve, external anal sphincter nerve, and the dorsal genital nerve, forexample. In some embodiments, the posterior tibial nerve can bestimulated transcutaneously in a manner similar to percutaneous tibialnerve stimulation but noninvasively and in a more prolonged manner. Insome embodiments, systems and methods include only transcutaneouselements without any implanted and/or percutaneous components.

Not to be limited by theory, voluntary control of the bladder can bemediated in large part by the autonomic nervous system (ANS). The ANSmaintains a balance which can be important to the normal functioning ofthe body's organs. For instance, the hypogastric nerve (sympathetic) andpelvic nerve (parasympathetic) both carry information about bladderfullness to the brain, and also work together to enable therelaxation-contraction mechanism that controls micturition. FIG. 1illustrates non-limiting structures and pathways associated with bladderfunction.

Activation of the pontine micturition center (PMC) results inparasympathetic activation of the bladder. This in turn contractsmuscles in the bladder and relaxes muscles in the urethra. Micturitioncommands cease when CNS structures including the periaqueductal gray(PAG) receive signals that the bladder is no longer full.

Inappropriate activation and inhibition of the parasympathetic andsympathetic systems can result in a sense of bladder fullness, urgency,sensory discomfort, and/or involuntary voiding. Peripheral stimulationthat affects the activity of autonomic nerves can be used to modulate orinterrupt micturition reflex circuits to correct abnormal bladderfunctioning. This modulation can be achieved by, for example,stimulation of the saphenous nerve, tibial nerve, or a combination ofthe two. In some embodiments, systems and methods use stimulationschemes designed to dephase, override or obscure the abnormal networks.In some embodiments, systems and methods use stimulation schemesdesigned to restore balance of sympathetic and parasympathetic activityof the micturition reflex loop. Advantageously, certain embodimentsutilize transcutaneous afferent stimulation of one, two, or moreperipheral nerves to modulate a brain or spinal pathway associated withbladder function, and/or an organ or target remote from the site(s) ofstimulation.

Generally, sympathetic fibers originate in the T11 to L2 segments of thespinal cord, while parasympathetic fibers originate in the S2 to S4spinal segments. The sympathetic fibers travel through the hypogastricnerve and inferior mesenteric ganglia, while the parasympathetic fiberstravel in the pelvic nerves and plexus. In some cases, effectivefrequency band for this parasympathetic modulation can be, for example,around the frequency band of 10 to 20 Hz, while the frequency bandsympathetic modulation can be, in some cases, as high as 30 Hz or as lowas 5 Hz. Not to be limited by theory, in some cases the higherfrequencies may offer benefit in comfort while the lower frequencies mayoffer benefit in better preservation.

In some embodiments, systems and methods involve stimulation parametersincluding frequency and spatial selectivity on the surface of the distallimb to selectively modulate and balance the sympathetic andparasympathetic system.

Not to be limited by theory, stimulation of a first target nerve, suchas the saphenous nerve can provide sympathetic modulation of the bladdercircuit. Specifically, electrical stimulation tuned to excite largemyelinated fibers in a target nerve, e.g., the saphenous nerve canprovide somatic afferent input to the lumbar plexus, mediating thesympathetic input to the bladder circuitry via the hypogastric nerve.Sympathetic nerves relax the detrusor muscle of the bladder by releasingnorepinephrine, activating the β adrenergic receptors, and contract theintrinsic urethral sphincter, by activating the α-adrenergic receptors.Relaxing the bladder and contracting the intrinsic sphincters can givecomfort during the filling and storage phases of the bladder cycle.Stimulation of a second target nerve, e.g., the tibial nerve can provideparasympathetic modulation of the bladder circuit. Specifically,electrical stimulation tuned to excite large myelinated fibers in thetibial nerve provides somatic afferent input to sacral plexus, thesacral micturition center, mediating parasympathetic input to thebladder circuitry via the pelvic nerves via release of cholinergictransmitters. There may also be input from the somatic efferents of thepelvic floor to the external urethral sphincter and modulates theafferent sensation of bladder fullness. Due to widely connected andcircuit-based mechanisms of these circuits, all mechanisms describedabove can in some embodiments modulate the central cortical and pontinemicturition centers which coordinate and time signals.

The system may run on a selection of pre-specified programs that varystimulation parameters and target one or more nerves individually or incombination to improve symptoms of overactive bladder in a specificpatient, e.g. whether their challenge is primarily daytime urinaryurgency, nighttime waking (nocturia), or incontinence. Alternatively,the system may be closed loop on a number of parameters including: thesubject's symptomatic history, including night waking events, ormanually entered urination indicated on board the device or a secondarydevice; direct detection of sympathetic and parasympathetic tone in thebladder or general circuitry, including HRV and galvanic skin response;and/or closed-loop based on previous usage of device, e.g., purelysympathetic excitation may be enhanced by brief periods ofparasympathetic balance.

In some embodiments, nerve stimulation can be synergistically combinedwith one, two, or more pharmacologic therapies for overactive bladder,including but not limited to an anti-cholinergic (e.g., oxybutynin,tolterodine, trospium, darifenacin, solifenancin, and/or fesoterodine),a beta-3 adrenergic (e.g., mirabegron), an anti-spasmodic (e.g.,flavoxate), and/or an anti-depressant (e.g., a tricyclic antidepressantsuch as desipramine or imipramine), a hormone (such as an estrogenand/or progesterone), or botulinum toxin.

Use of chronic, noninvasive stimulation can involve certain waveformcharacteristics to excite sensory neurons in a comfortable manner. Thefrequency of stimulation used can be, for example, within the betweenabout 1 Hz and about 500 Hz range (such as, for example, between about 5Hz and about 30 Hz, such as between about 10 Hz and about 20 Hz) orbetween about 1 kHz and about 100 kHz to preferentially affect theproper targets. In some embodiments, the waveforms can be biphasicrectangular or balanced in charge in order to minimize irritation to theskin, such as illustrated schematically in FIG. 1A. In some embodiments,waveforms could also be asymmetric, especially in the case to stimulateone, two, three, or more nerves as described in, for example, U.S. Prov.App. No. 62/360,265 filed on Jul. 8, 2016, which is incorporated byreference in its entirety. In some embodiments, waveform shapes andrising edges can be altered in order to increase patient comfort andtolerability to the treatment. In some embodiments, the waveforms caninclude higher frequency sine waves carried inside the rectangularsignal as illustrated in FIG. 1B. An interval between the opposite-goingwaveforms can be adjusted to a value that allows for charge balance,while allowing the first waveform's excitatory effects to not beimmediately negated by the second waveform, but balancing the charge atthe interface to reduce skin irritation and improve comfort. In somecases, spacing between 0 microseconds to 300 microseconds has beeneffective. The waveform amplitude can be adjusted so that it isperceptible, above a minimum sensation threshold, but not intolerable tothe patient.

In some embodiments, the effector can be excitatory to the nerve. Inother embodiments, the effector can be inhibitory to the nerve. In someembodiments, the system can be used to excite the nerve during someportions of the treatment and inhibit the nerve during other portions ofthe treatment.

In some embodiments, waveforms including those described herein can bemodified over time in order to minimize certain effects, such ashabituation. One way of decreasing habituation is to modify thefrequency, pulse width, or amplitude of the stimulation. For instance,randomizing or pseudo-randomizing parameters such as, for example, thefrequency or pulse width can reduce habituation. Using a Gaussiandistribution for randomization can be effective in some cases, and usedin such waveforms as stochastic waveforms. Another way of reducinghabituation is to the lower the frequency below a certain threshold,such as, for example, no more than about 60 Hz, 55 Hz, 50 Hz, 45 Hz, or40 Hz, in which humans tend not to habituate.

Varying other parameters such as amplitude can be a way to improvewaveform comfort. For example, the amplitude of the stimulation can beadjusted based on the threshold necessary to produce strong sensoryperception and paresthesia without eliciting motor contraction.Excitation of muscles can lead to unpleasant cramping sensations in someembodiments. This amplitude could also be modulated throughout a sessionto be the appropriate, comfortable value depending a person's positionor motion.

The stimulation waveforms described herein can be applied continuouslyto target nerves such as the tibial and/or saphenous nerves, forexample, or can be provided in a manner that is adaptive in applyingstimulation of various durations or by adjusting properties of thestimulation waveform, including but not limited to amplitude, frequency,and pulse width, in response to different inputs in the system. In someembodiments, the system could include closed loop control, using one ormore signals measured by the device or feedback input into the device bythe patient or physician to modulate the stimulation to improveefficacy. The signals or input could include, for example, any number ofthe following: sensors on-board the device or connected in the digitalecosystem; evaluation of autonomic function, reflex loop integrity, orexcitability using heart rate variability, measuring muscle sympatheticnerve activity (MSNA), and/or measuring h-reflex by sending astimulation signal and measure response with EMG. In some embodiments,the signals or input can also include sleep sensor sets, including butnot limited to accelerometers, gyroscopes, infrared based motionsensors, and/or pressure sensors under a mattress, to measure night timemotion as a measure of nocturia events. For example, patients may wear astimulator while sleeping and therapy can be triggered by night timerestlessness, which is an indicator of an upcoming nocturia event. Amotion sensor set (e.g., accelerometer, IR based motion sensor, etc.)can measure rapid back and forth movement of legs typically seen whensomeone has a sense of urgency. An EEG headband could be used to measuredifferent sleep states. Patient and/or physician input can providefeedback on the effectiveness of and/or satisfaction with the therapyinto the device or into another connected device. Also, usage of thestimulation device can be tracked; and specific stimulation programs(e.g., a specified set of stimulation parameters) can be changed basedon symptoms presented by the patient or outcomes of the therapy.

In some embodiments, a stimulator can be part of a system with sensorsto assess the state of sleep and modulate stimulation based on thewearer's sleep state. Sensors could include motion sensors (e.g., bodyworn accelerometers and gyroscopes, or wireless motion tracking viavideo or infrared), temperature sensors to measure body temperature,pressure sensor under the mattress to measure movement, heart ratesensors to measure HRV, other sensors to measure sympathetic andparasympathetic activity, and/or EEG sensors to measure brain activityto assess the wearer's sleep state. For example, if nocturia eventsoccur during slow wave sleep when parasympathetic activity can beelevated, stimulation parameters are modulated to affect parasympatheticactivity, and vice-versa for sympathetic activity.

In some embodiments, a first stimulation frequency can be provided forshort term benefit, and a second stimulation frequency different (e.g.,higher or lower) from the first stimulation frequency can be providedfor long-term benefit. For example, 10 Hz stimulation can provide ashort term benefit and 20 Hz stimulation can provide a long term benefitin some cases. As one example, 10 Hz stimulation can be provided in aninitial period with the therapy (e.g., 3 weeks) for acute therapy, then20 Hz stimulation can be provided for long term maintenance or conditiontherapy, or vice versa depending on the desired clinical result. In someembodiments, particular sympathetic and/or parasympathetic nervoussystem targets and circuits can be specifically targeted to modulateupward or downward sympathetic and/or parasympathetic nervous systemactivity depending on the patient's underlying autonomic nervous systemactivity. Utilization of data and/or sensors directly or indirectlymeasuring sympathetic and/or parasympathetic nervous system activity asdisclosed, for example, elsewhere herein can be utilized as closed loopfeedback inputs into a hardware and/or software controller to modifystimulation parameters, including on a real-time basis.

In some embodiments, the therapy (e.g., stimulation) can be applied forabout, at least about, or no more than about 5 minutes, 10 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5hours, 6 hours, or more a day. In some embodiments, the patient istreated nocturnally, such as during sleep, and/or during waking hours.The treatment can be repeated 1, 2, 3, 4, 5, or more times daily orweekly, every other day, every third day, weekly, or other intervaldepending on the desired clinical result.

In some embodiments, the responsiveness could be dependent on differenttimes of day. For instance, the patient or physician (or algorithm)could pre-schedule different episodic treatment sessions throughout theday and the device could provide treatment stimulation at thosedifferent times of day. In one example, treatments are applied atregular or irregular intervals during the day at a frequency related tothe typical amount of voiding. In the treatment of nocturia, stimulationcould be timed to periodic intervals during a person's sleep. In someembodiments, stimulation schemes are applied to restore autonomicdysregulation based on natural diurnal patterns of sympathetic orparasympathetic activity. Treatment could also occur at irregularintervals that are human-entered or predicted by machine learning fromprevious days' voiding incidents. In some embodiments, a first frequency(e.g., 10 Hz or 20 Hz) therapy can be applied in the morning for acuteday time relief, and a second different higher or lower frequency (e.g.,20 Hz or 10 Hz) therapy can be provided before bed for longer night timerelief.

In some embodiments, the responsiveness could be dependent on activity.For instance in nocturia, a motion sensor such as an accelerometer orgyroscope could sense if a person is stirring, which could indicate adesired potential voiding. During that time, the device could turn on toprovide appropriate stimulation. In some embodiments, the device couldturn off once voiding is complete.

In some embodiments, the responsiveness of stimulation could bedependent on one, two, or more sensors housed in the device to collect,store, and analyze biological measures about the wearer including, butnot limited to, motion (e.g., accelerometers, gyroscopes, magnetometer,bend sensors), ground reaction force or foot pressure (e.g., forcesensors or pressure insoles), muscle activity (e.g., EMG),cardiovascular measures (e.g., heart rate, heart rate variability(HRV)), skin conductance (e.g., skin conductance response, galvanic skinresponse), respiratory rate, skin temperature, and sleep state (e.g.,awake, light sleep, deep sleep, REM). Using standard statisticalanalysis techniques, such as a logistical regression or a Naïve Bayesclassifier, these biological measures can be analyzed to assess thewearer's activity state, such as sedentary versus active, level ofstress and/or bladder fluid volume, and the like, which in turn, canserve as a predictor for increases in urinary urgency.

Sympathetic and parasympathetic activity can be measured through severalmethods, including microneurography (MSNA), catecholamine tests, heartrate, HRV, or galvanic skin response. HRV can provide a quick andeffective approximation of autonomic activity in the body. HRV can bedetermined by analyzing the time intervals between heartbeats, alsoknown as RR intervals. Heart rate can be accurately captured, forexample, through recording devices such as chest straps or fingersensors. The differences between successive RR intervals can provide apicture of one's heart health and autonomic activity. Generallyspeaking, healthier hearts have more variability between successiveRR-intervals. This interbeat data can also be used to denote anindividual's sympathetic and parasympathetic activity levels. Throughfrequency-domain analysis, heartbeat frequencies can be separated intodistinct bands. High-frequency signals (˜0.15-0.4 Hz) almost exclusivelyreflect parasympathetic activity, and low-frequency signals (˜0.04-0.15Hz) represents a mixture of sympathetic and parasympathetic activity.Therefore, taking the ratio of high frequency (HF) to low frequency (LF)signals yields an approximation of one's sympathetic tone. In someembodiments, HRV can be analyzed, for example, under time-domain,geometric domain methods in addition to frequency domain methods. Insome embodiments, increased heart rate variability can signify increasedparasympathetic response and/or decreased sympathetic response.Decreased heart rate variability can signify decreased parasympatheticresponse and/or increased sympathetic response. In some embodiments, asystem can sense an increase or decrease in HRV of about or more thanabout 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, 100%, ormore over a baseline value (or target desired HRV value) and institute achange in one, two, or more stimulation modality parameters accordingly.In some embodiments, the one, two, or more stimulation modalities can beconfigured to modulate, such as increase or decrease stimulation to oneor more nerves (e.g., peripheral nerves) associated with the sympatheticand/or parasympathetic nervous system, and a response to therapy can beconfirmed by sensing an increase or decrease in parasympathetic orsympathetic tone, including but not limited to increase or decrease inHRV, changes in high frequency content of HRV, and changes in the ratioof high frequency and low frequency content of HRV.

In some embodiments, balance of parasympathetic and sympathetic activityof the bladder reflex loop can be assessed with frequency analysis ofheart rate variability measured with pulsed plethysmography with an LEDlight source and optical sensor disposed in the device that measuresfluctuations in light level due to blood flow that target one of themajor blood vessels around the knee, which could include one or more ofthe following, femoral, popliteal, posterior tibial, anterior tibial,and/or descending genicular arteries or veins.

A large source of error in optical measurements of heart rate is motionartifacts due to relative motion between the optical sensor and theblood vessel being measures. In some embodiments, the optical heart ratesensor has an adhesive on the side of housing that contacts the wearer'sskin to reduce relative motion between the sensor and the target bloodvessel.

In some embodiments, one, two, or more additional sensors are disposedin the device, including electrical sensors in contact with the wearer'sskin to measure cardiac activity or pressure sensors to measure changesin blood vessels, to be used in combination with an optical sensor toimprove the fidelity of heart rate measurement.

In some embodiments, the system and device have memory and a processorto extract RR intervals from sensor data, calculate variability of RRintervals, transform data into frequency domain, and calculate highfrequency signals, low frequency signals, and the ration of the highfrequency and low frequency signals.

In some embodiments, the heart rate sensor store collected data forspecified time period to gather adequate date for heart rate variabilitycalculation. Specified time period can range in some cases from 1-60seconds, and may extend to 10 minutes.

In some embodiments, electrodermal activity, also known as galvanic skinresponse or skin conductance response, for example, can be measuredusing sensors, such as electrodes. Galvanic skin response is the changeof the electrical resistance of the skin caused by emotional stress, andmeasurable with, e.g., a sensitive galvanometer. Not to be limited bytheory, skin resistance varies with the state of sweat glands in theskin. Sweating is controlled by the sympathetic nervous system, and skinconductance can be an indication of psychological or physiologicalarousal. If the sympathetic nervous system is highly aroused, then sweatgland activity also increases, which in turn increases skin conductance.In this way, skin conductance can be a measure of emotional andsympathetic responses, which can be measured, and the feedback data canbe sent to the controller, which will in turn modulate stimulation to,for example, decrease sympathetic nervous system activity. Othernon-limiting parameters associated with sympathetic and/orparasympathetic nervous system activity that can be sensed include, forexample, sweating during particular times of the day and/or night, sleepstates as detected, for example, by an EEG headband (to determine whensympathetic and/or parasympathetic activity is particularly high or low,and potentially correlating a sleep state such as stage 1, 2, 3, 4, orREM with nocturia), and/or motion.

The device could also be responsive to number of episodes of symptoms,including overactive bladder. If more episodes occur in one day,treatment can be increased by increasing the amplitude of thestimulation, duration of the stimulation, or number of treatmentsessions, for example.

The number of episodes of symptoms such as overactive bladder could bedetected in various ways to control the stimulation applied by systemand devices. In some embodiments, the patient can enter events relatedto symptoms of overactive bladder, including but not limited to bladdervoiding events, urgency event, or incontinence events on a mobiledevice. In some embodiments, location services on the device, such asGPS, can detect when the person has entered a building or bathroom.

Information regarding bladder voiding can be combined in someembodiments with an understanding of the amount of fluid a person hasconsumed in order to better apply a desired amount of treatment. Forexample, in days where more beverages were consumed by an individual,more bladder voiding would be expected. FIG. 2 schematically illustratesa flow chart incorporating a stimulation protocol, according to someembodiments of the invention. The times, amounts, and types of beveragesingested by a patient over the day can be recorded manually orelectronically, such as in a software application, as shown in box 200.Knowing when and what was consumed can be used to predict when and howmuch a person's bladder should be emptied and the amount of treatmentcan be applied accordingly. The information regarding the processingtime of a certain amount of liquid in the human body could be used toanticipate through literature studies with additional information fromthe patient (such as gender, weight, and height, and potentiallymeasuring bladder size using an initial pelvic ultrasound procedure).This processing and consolidation of data (shown in box 202) toanticipate the amount and timing of treatment necessary can be donewithin a single device or utilizing another separate device, forinstance a mobile phone. In this manner, stimulation 204 can be appliedaccordingly based on the number of episodes a person experiences.

One method of recording the times and types of beverages consumed isthrough a journal or diary, for example on a smartphone, tablet, orother device. Another method of achieving this is to use a device suchas a smart cup that identifies the types and amounts of beveragesconsumed through the day and syncs this information to the system ordevice. This information can advantageously be an automatic journal ofthe amount of liquids consumed through the day.

Bladder control and comfort require a delicate balance of sympathetic,parasympathetic, somatic efferent and afferent innervation of thebladder reflex circuits. In some embodiments, a variable frequencystimulator in electrical connection with three or more electrodes totarget at least two nerves that provide sympathetic, parasympathetic andsomatic input into the bladder reflex circuits. In some embodiments, thedevice is disposed in a knee strap fitted just below the knee with afastening mechanism to hold the device securely on the body. In someembodiments, the electrodes, constructed from an adhesive hydrogel, aredisposed in the housing of the device allowing the device to adhere tothe wearer's skin.

In some embodiments, as shown schematically in FIG. 3, the nervestimulator can be designed like a calf band 357 having a stimulatorhousing 359 attached thereto and configured to be positioned just distalto the knee for stimulating the posterior tibial nerve and the saphenousnerve transcutaneously. As illustrated in FIGS. 4A-4B, the nervestimulator can include an ankle brace or anklet 400 with a stimulatorbox 402 (shown in FIG. 4A) or an ankle brace (shown in FIG. 4B). Thisform factor could also be extended to a sock, shoe, boot, or stockingfor example. These form factors can be advantageous in some cases, asthey are compact and do not necessarily interfere with gait. Theelectrodes can be integrated into a garment in the form of conductivepolymers or silver fabrics, for example. In some embodiments, dryelectrodes can be utilized, such as dry electrodes that include aconductive backing layer (e.g., a metal foil material, such as disposedon a flexible polymer substrate) and a skin contact layer disposed onthe conductive backing layer, that can include for example a polymer,plastic, or rubber material, and a conductive filler material (e.g.,powder, fine particulate material, metal, carbon, mixtures thereof, orporous material treated with a conductive coating) dispersedsubstantially evenly throughout the silicone, plastic, or rubbermaterial. In some embodiments, the skin contact layer has a skin facingsurface that is not coated with a hydrogel or liquid.

In some embodiments, the weave of the brace or sock could be designed toprovide tight pressure at the knee, calf, ankle, or other desired regionof the device, similar to the weave of commonly found anklet socks.Electrodes can also be made from, for example, conventional hydrogels.In some cases, a clasp or fastening element such as Velcro may be neededbecause with sticky electrodes, the device cannot be easily slid on thefoot. In some embodiments, the, e.g., knee, calf, ankle brace or ankletembodiments can be extended to electrode positions that are on the top(dorsal) or bottom (ventral) surfaces of the foot. In some cases, a sockwith electrodes on the sole of the foot can be used with connectivitythrough the sock to an electronics module located near the ankle.

FIGS. 5A-5C illustrate non-limiting embodiments of potential electrodeplacement locations for nerve stimulation. The sensor systems, includingthose disclosed herein can communicate via wires or wirelessly to thestimulator 502. Placement of the electrodes of the tibial stimulatorcould vary with electrodes 500 placed along the tibial nerve (FIG. 5A),at the bottom of the foot (FIG. 5C), or on either side of the ankle orattached to a stimulator (FIG. 5B).

In some embodiments if the electrodes 606 are sticky, as shown in theembodiment of FIGS. 6-7, a device 600 in the form of a bandage can bemade, which circumferentially or non-circumferentially envelop a portionof a body part, such as an extremity. The strip can be any shape,including an annular, square, rectangular, triangular, or other shape.In some cases, the electronics can be located inside a removable housing602 that can be removably attached at site 604 from the entire device600 when the disposable is thrown away. FIG. 6 is a bottom view, whileFIG. 7 is a top view of the device 600.

In another embodiment, as illustrated in FIG. 8, a thin, bandage-likeelectrode 802 can be attached to the patient. Power can be coupled froma battery source that is loosely wrapped around the target body region,such as the knee or ankle for example, like a knee band, thigh band,calf band, an anklet 800 or sock, or located on the side of the shoe inthe general vicinity of the electrode. In some embodiments, power can bedelivered wirelessly to the electrode 802, such as via inductivecharging. This configuration can be advantageous, in some embodiments,in that the disposable can be made very thin, increasing the comfort ofthe skin interface even if the disposable is very sticky (this isanalogous to an adhesive bandage). This embodiment can also be adaptedfor use if the electrode bandages are placed on the bottom of the foot.In some cases, the electronics could be located/clipped on the top of ashoe or in the sole of the shoe.

Several peripheral nerves in addition to, or instead of the tibial nervecan serve as targets for urinary neuromodulation, including the pudendaland dorsal genital nerve, with acute and/or chronic effects on bladderfunction in animal and human experimental studies. Saphenous nervestimulation can acutely or chronically reduce bladder hyperexcitability.The saphenous nerve is a purely sensory nerve that innervates the skinon the medial lower leg. Its proximity to the skin surface makes it anadvantageous target in some embodiments for transcutaneous stimulation.Selective stimulation of the saphenous nerve can in some embodimentsadvantageously reduce overactive bladder symptoms. In some embodiments,peripheral nerves can be independently targeted with specific same ordiffering frequencies to prove acute or chronic relief of symptoms ofoveractive bladder, and/or to alter sympathetic and/or parasympatheticactivity.

The effects of peripheral nerve stimulation on bladder function mayoccur only during the period of active stimulation in some embodiments,or may outlast the stimulation period after stimulation has ceased.Different mechanisms such as the modulation of urinary reflexes orinduction of brain and/or spinal plasticity can be triggered usingsystems and methods as disclosed herein. Furthermore, in some cases theonset of the effects of stimulation may occur acutely or only afterseveral stimulation sessions in a chronic manner. For example, theeffect of transcutaneous or percutaneous tibial nerve stimulation onpatient related outcomes is estimated in some embodiments at 4-6 weeksafter the initiation of weekly stimulation sessions. Depending on theunderlying mechanisms and the time course of beneficial effects,stimulation may require delivery in a continuous fashion such as insacral nerve stimulation, in discrete scheduled sessions or in anon-demand, conditional manner. Conditional stimulation may either relyon patient control to identify the sense of urinary urge or automateddetection of an involuntary detrusor contraction (IDC) which isresponsible for urgency symptoms or evolution to frank incontinence.

Conditional stimulation of the dorsal genital nerve and/or pudendalnerve can be advantageous in some embodiments. Alternatively or inaddition, continuous stimulation can be utilized to control bladdersymptoms. The advantages of conditional stimulation in some embodimentscan include customization of symptom control, improved battery life, andreduction of the risk of habituation with continuous stimulation. Apatient controlled conditional stimulation device for overactive bladdermay be effective for suppressing urge symptoms prior to the progressionto incontinence.

The stimulation frequency can be varied depending on the desiredclinical result. In some embodiments, a relatively higher frequency,such as between about 10 Hz and about 33 Hz, between about 10 Hz andabout 30 Hz, between about 10 Hz and about 20 Hz, or between about 20 Hzand about 33 Hz, or about or at least about 10 Hz, 15 Hz, 20 Hz, 25 Hz,30 Hz, 33 Hz, 35 Hz, or more can be used. The stimulation frequency canalso be tailored to the specific nerve targeted. In some embodiments,lower stimulation rates such as 2 Hz can have an excitatory effect onbladder function and worsen incontinence. However, in some embodiments,a frequency of about or no more than about 10 Hz, 9 Hz, 8 Hz, 7 Hz, 6Hz, 5 Hz, 4 Hz, 3 Hz, 2 Hz, or 1 Hz can be utilized. In someembodiments, the stimulation frequency could be in the kHz range, suchas, for example, between about 1 kHz and about 100 kHz, such as betweenabout 10 kHz and about 50 kHz. The stimulation could be regular,irregular, or random in some embodiments. In some embodiments, afrequency or a plurality of frequencies for one, two, or more nervescould be selected from, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 35, 40, 45, 50 Hz. In some embodiments, two or more of thesame or different frequencies or frequency ranges can be applied to thesame or different target nerves.

The exact location of stimulation in the lower leg can vary depending onthe desired target. For example, the tibial nerve may be stimulated atthe level of the ankle or behind the knee. As the saphenous nerveterritory is over the medial lower leg, stimulation of the nerve may beachieved at the ankle or closer to the knee in some cases.

In some embodiments, stimulation of the saphenous nerve can be usedinstead of or in conjunction with tibial nerve stimulation to treatoveractive bladder and/or urinary incontinence. The saphenous nerve runsthrough the upper leg, descends along the medial side of the knee,descends along the tibial side of the lower leg and divides into twobranches, a branch that continues to descend along the tibia thatextends to the ankle and a branch that passes in front of the ankle andextends along the medial side of the foot.

In some embodiments, a stimulator worn around the ankle or lower leg orknee or upper leg can be used to stimulate the saphenous nerve and,optionally, also the tibial nerve. In other embodiments, the stimulatorcan be worn around any other part of the leg or foot in order tostimulate the saphenous nerve at other locations. The electrode(s) ofthe stimulator can be placed proximate or over the saphenous nerve.

In some embodiments, the stimulation can be electrical and be providedtranscutaneously using an electrode placed on the patient's skin. Insome embodiments, the stimulation of the saphenous nerve can be patientactivated. In some embodiments, the stimulation of the saphenous nervecan be automated and/or patient activated. In some embodiments, thestimulation of the saphenous nerve can be solely patient activated,meaning the stimulation is only provided while the patient is awake. Ifstimulation while the patient is asleep is desired, an automatedstimulation regimen can be provided.

FIG. 9 illustrates an embodiment of a distal saphenous nerve sensingand/or stimulation technique. In some embodiments, the therapy can beperformed in a supine, upright, or sitting position. In someembodiments, a bar electrode (e.g., 3 cm) can be used. A referenceelectrode (R) can be positioned slightly anterior to the highestprominence of the medial malleolus, between the malleolus and the tendonof the tibialis anterior. The active electrode (A) can be positionedproximal and slightly medial to the tibialis anterior tendon. A return,e.g., ground electrode (G) can be placed, for example, between therecording electrodes and the cathode. With regard to the stimulationpoint (S), the cathode (C) can be placed, for example, 14 cm proximal tothe active electrode deep to the medial border of the tibia. The anode(A) can be, for example, proximal. In some embodiments, the devicesettings could include any of the following: Sensitivity—2-5μV/division, Low frequency filter—20 Hz, High frequency filter—2 kHz,Sweep speed—1 msec/division. In some embodiments, the L3 and L4 nerveroots, through the posterior division of the lumbosacral plexus, can betested. In some embodiments, sensing and its associated components suchas the reference electrode (R) may not be required.

In some embodiments, a device for stimulating one, two, or more nervesis illustrated schematically in FIG. 10. The device 10 can include ahousing 20 and one, two or more effectors 30, power sources 50, and/orcontrols 40. In some embodiments, the device further includes one ormore sensors 70. The effectors can include a pulse generator andelectrodes for delivering electrical stimulation, and/or can be amechanical stimulator for delivering mechanical stimulation, such asvibratory stimulation, for example. The sensors can include, forexample, accelerometers, gyroscopes, and electrodes to measureelectrical activity including nerve activity and muscle activity.

In some embodiments, as illustrated in FIG. 10A, the device can includea 2D or 3D array of electrodes 1000 such that the stimulation may betargeted. The elements 1002 may be individually addressable such thatthe location of stimulation can be adjusted on-the-fly or for eachsession, such as electronic referencing. Alternatively, the elements maybe configured for an individual user, such as a mechanical configurationin which the electrode connections are cut or spliced to customize thedevice.

FIG. 10B illustrates an embodiment of a stimulation system 1001including a wearable device 1010 on the ankle or other desiredanatomical location, as well as an implanted stimulation electrode 1020around a target nerve 1030, such as the tibial nerve for example. Inanother embodiment, the wearable device may be a component of astimulation system including subcutaneous, transcutaneous, and/orpercutaneous components. For example, the wearable device maycommunicate with an implanted stimulation device to power and controlthe device. Additionally, the implantable electrode can be powered by arechargeable battery housed within the implant and recharged wirelesslyfrom an external power source or the wearable device. Alternatively, thewearable may contain a guiding array used to direct the location ofpercutaneous needles either in a patient-directed or healthcare setting.

In some embodiments, an implanted electrode that stimulates the nervecan be powered by an external stimulation unit, and the stimulationpulse is directly coupled to the electrode and nerve using capacitive orinductive coupling. In some embodiments, the wearable device cancommunicate with an external computer or device (e.g., tablet,smartphone, smartwatch, or custom base station) to store data.Communication between the wearable device and external device can be adirect, physical connection, or with a wireless communication connectionsuch as Bluetooth, Wi-Fi, Zigbee, GSM, or cellular for example. In someembodiments, the system communicates with an external, portablecomputational device, such as a smartphone via an app, or other mobiledigital interaction. The device may be used to track information ofrelevant events either user-entered or automatically captured frombiological sensors, such as the time since the last urination and fluidintake, or biometric data predicting upcoming episodes of urinaryincontinence or urinary urgency. This information may be used to closethe loop to adjust stimulation parameters (waveforms, amplitude, on/off)or suggest user behaviors.

In some embodiments, the wearable device can have a GPS or similardevice to track the location and assess activity of the wearer. GPSmeasures can be combined with mapping or location systems to determinecontext of the wearer's activity (e.g., gym versus office) or determinechanges in elevation during specific activities, such as running orcycling.

In some embodiments, the wearable device can track parameters aboutstimulation provided by the stimulation unit, including time ofstimulation, duration of the stimulation session, and power used by thestimulation unit. This data can be stored on memory in the wearabledevice, processed by the wearable device, and/or transmitted to anexternal computing device.

The stimulation unit can use switches or electrical sensor to detectconnection of electrodes: (1) to ensure proper and unique electrodes arebeing installed (e.g., not using a different or incorrect type ofelectrode) communicating a unique code, for example via RFID, (2) toregulate the number of uses for each electrode to prevent over use,and/or (3) to prevent the usage of the device without an electrode toprevent small shock.

In some embodiments, a system may include features to increase skincomfort. One solution is to use a high frequency carrier (e.g., kHz suchas 1 kHz or greater) wave over the low frequency beats (10 to 200 Hz),or to position electrodes such that the interaction of two waveformscombines to produce a low frequency beat.

In some embodiments, systems and methods of peripheral nerve stimulationcan be provided that target one, two, or more individual nerves asillustrated in FIGS. 11A-11E. In some embodiments, the system 10 canthat allows customization and optimization of transcutaneous electricaltreatment to an individual. In particular, the device 10 described isfor electrical stimulation of one, two, or more nerves. For example, atwo electrode embodiment can be used to stimulate the tibial and/orsaphenous nerve. Targeting these specific nerves and utilizingappropriately customized stimulation can in some embodiments result inmore effective therapy. In some embodiments, the target nerves caninclude nerves in the leg, e.g., the tibial and/or saphenous nerve, thatcan be used to treat overactive bladder. In some embodiments, the device10 can be configured to be worn on the leg, knee, or ankle and can beformed from a housing 12 and a band 14 or sleeve. In some embodiments,electronics and sensors located in a housing 12 can measure indicationsof bladder fullness or other symptoms of overactive bladder, asdescribed herein. The electronics can include, for example, a pulsegenerator, a controller, and one, two, or more sensors such as anaccelerometer and/or gyroscope and/or electrodes for measuring nerveactivity. Electrical contacts and/or traces in the band 14 and/orhousing 12 transmit the stimulation waveform from the pulse generator tothe electrodes 16, which can be disposable. The location of the contactsin the band 12 can be arranged such that specific nerves are targeted,such as the tibial and/or saphenous nerve, or others including thosedisclosed herein. The housing 12 also can have a digital display screento provide feedback about the stimulation and sensor data to the wearerof the device.

In some embodiments, disclosed herein is a dual nerve stimulator withthe entire device or a portion thereof configured to be positioned justbelow the knee to target the saphenous and posterior tibial nerves,including sensors for measuring slow changes in heart rate variabilityto assess autonomic dysregulation (e.g., to balance sympathetic andparasympathetic activity), and/or accelerometry for measuring overallactivity, where the nerve targeted and the frequency of stimulation arecontrolled based on sensor data. Stimulation of each of the targetnerves can be turned on or off independently, and the stimulationfrequency can be adjusted independently to provide acute or chronicrelief of symptoms due to a condition such as overactive bladder, asneeded.

In some embodiments, the treatment device 10 can be a wearable deviceincluding an electronics box or housing 12 containing the stimulator orpulse generator 18, sensors 20, and other associated electronics such asa controller or processor 22 for executing instructions, memory 24 forstoring instructions, a user interface 26 which can include a displayand buttons, a communications module 28, a battery 30 that can berechargeable, and optionally an inductive coil 32 for charging thebattery 30, and the like. The device 10 can also include, for example, aband or sleeve to hold all the components together and securely fastenthe device around the leg, knee, foot, or ankle of an individual. Thedevice can also include, for example, a pair of electrodes on the bandor sleeve.

Additional system and device embodiments are shown in FIGS. 12 and 13,which show that the electrodes can be disposed on a wearable band (orsleeve) that can be circumferential or non-circumferential, and wornaround the ankle, knee, leg, or other body part. The wearable band mayinclude a removable/detachable controller as further described inInternational Application No. PCT/US2016/37080, titled SYSTEMS ANDMETHOD FOR PERIPHERAL NERVE STIMULATION TO TREAT TREMOR WITH DETACHABLETERHAPY AND MONITORING UNITS, which is hereby incorporated by referencein its entirety for all purposes. As shown, the wearable bands have twoelectrodes which can be used to stimulate up to two nerves. However,other embodiments can have N electrodes to stimulate up to N nerves, orN+1 electrodes to stimulate N nerves (e.g., 2 electrodes to stimulate upto 1 nerve; 3 electrodes to stimulate 2 nerves; or 4 electrodes tostimulate 3 nerves).

FIG. 12 illustrates a wearable band 800 with disposable electrodes 802,804. The disposable electrodes 802, 804 can be coated or covered with anelectrically conductive hydrogel and may be disposed on a strip 806 thatcan be removably attached to the wearable band 800, which may have areceptacle 808 for receiving the strip 806. The strip 806 and the band800 can have electrical contacts and a flexible circuit so that theelectrodes are electrically connected to the controller 810. Toaccommodate various body part sizes, the disposable strip 806 can beprovided with a variety of electrode spacings. This allows one band sizeto accommodate users with different body part sizes. Since hydrogels candry out, hydrogel coated electrodes may be more suitable for use withremovable electrodes, as shown in FIG. 12, that can be disposed andreplaced on a regular basis, such as every 1, 2, 3, 4, 5, 6, or 7 days.

In some embodiments, stimulating three or more electrodes can be used tostimulate two or more nerves. In some embodiments as shown in FIG. 12A,the electronics and electrical circuit 1200 used to drive the array caninclude an adaptable switch that allows each individual electrode 1202to be connected to either one of the two contacts 1204, 1206 of thestimulator 1208 at a given time by opening or closing switches 1210 ineach channel. Each channel can include a DC blocking circuit 1212, ascharge balance can be important to prevent skin irritation and bums, andalso be individually current limited by current IO limiters 1214 inorder to prevent current surges that could cause injury or discomfort.This current limitation can be set to a predetermined tolerabilitythreshold for a particular patient or group of patients.

There are many transistor circuits or components like polyfuses to limitor shutdown the current to a particular node. These circuits and itscomponents, such as the stimulator, switches, and current limiters, canbe controlled and/or be programmable by a microprocessor 1216 inreal-time. The 15 switch matrix allows multiple electrodes to beconnected to the same stimulator contacts at a given time for maximumflexibility. In addition, electrodes can be switched between thepositive and negative contacts of the stimulator to produce a bipolarpulse.

FIG. 13 shows an embodiment of a wearable band 900 with integratedelectrodes 902, 904. The integrated electrodes 902, 904 can be dryelectrodes in electrical communication with a detachable controller 910through a flexible circuit embedded in the band. In some cases, dryelectrodes may be more suitable for longer term use electrodes that canbe used for months, such as at least 1, 2, or 3 months, before the bandneeds to be replaced. In some embodiments, the band may be a single useband that can be used for a relatively long period of time beforereplacement.

In some embodiments, disclosed herein are systems and methods forstimulating a plurality of nerves for the treatment of conditionsincluding but not limited to overactive bladder. Stimulation of 2, 3, ormore nerves, such as the saphenous and tibial nerve could be used forthe treatment of conditions such as overactive bladder. Dual nervestimulation can in some cases synergistically increase the effectivenessof therapy by combining synergistically the effects of, for example,saphenous and tibial nerve stimulation. In some embodiments, includingthose disclosed in connection with FIGS. 14 and 15 below, the system canbe configured to independently control stimulation of a first targetnerve (including stimulation parameters such as frequency and otherslisted herein) and a second target nerve respectively. In other words,the first target nerve and the second target nerve can be stimulatedwith either the same or different parameters, and can be stimulatedsimultaneously or in alternating or other fashion. In some embodiments,the stimulation systems can include a plurality of independentstimulation circuits, or a common circuit with a controller configuredto switch stimulation parameters for one, two, or more nerves.

In some embodiments, as illustrated schematically in FIG. 14, a system1400 can utilize three electrodes: a first electrode 1404 positionedover a first nerve, e.g., the tibial nerve 1402, a second electrode 1406positioned over a second nerve, e.g., the saphenous nerve 1408, and athird electrode 1410 positioned, for example, on the outer side of theleg, opposite to the first two electrodes 1404, 1406. This thirdelectrode 1410 would serve as a common cathode for the other twoelectrodes 1404, 1406. The three electrodes 1404, 1406, 1410 can beoriented in such a way that the electric fields between each of thefirst two electrodes 1404, 1406 and the common cathode 1410 pass throughthe tibial nerve 1402 and saphenous nerve 1408, respectively.

Another possible configuration shown in FIG. 15 utilizes fourelectrodes. Similar to the embodiment illustrated in FIG. 14, threechannels are used: a first targeting the tibial nerve 1402, a secondtargeting the saphenous nerve 1408, and one acting as a common cathode1410. However, the cathode in the electronics is split between twocommon electrodes 1411, 1413, each serving as a cathode electrode forthe other two electrodes 1404, 1406. Thus, a first electrode 1404 ispositioned over the tibial nerve 1402 with a first cathode electrode1411 positioned directly below it and a second electrode 1406 ispositioned over the saphenous nerve 1408 with a second common electrode1413 positioned directly below it. Each electrode pair 1404, 1411 and1406, 1413 can be oriented in such a way that the electric field betweenthe two electrodes (the electrode over the nerve and its respectivecommon electrode) passes through the intended nerve (e.g., tibial orsaphenous).

A 4 week proof of concept (POC) study of transcutaneous saphenous nervestimulation was performed, and 7 subjects were enrolled. Eligibility wasconfirmed using industry-standard OAB-V8 screen and a week of baselinedata. The subjects were treated with 60 minutes of daily saphenous nervestimulation. Data collected included a weekly 3-day voiding diary, andICIQ-SF and OAB-Q patient assessments at a 4 week appointment. The studydata is shown in FIGS. 16A-16C. FIG. 16A illustrates bar graphs showingthat patients responded after 1 week of daily therapy, faster than the 4week response reported for percutaneous stimulation. All subjectsimproved, and 4 subjects with mild to moderate incontinence experiencednear-complete alleviation of incontinence. FIG. 16B illustrates thatnocturia generally improved as well. FIG. 16C shows results of the OAB-qscale, an established scale for quality of life in overactive bladder,and demonstrates clinically significant (e.g., 10 point or more)improvement in quality of life.

A 4 week proof of concept (POC) study of transcutaneous tibial nervestimulation was performed, and 4 subjects were enrolled. Eligibility wasconfirmed using industry-standard OAB-V8 screen and a week of baselinedata. The subjects were treated with 60 minutes of daily tibial nervestimulation. Data collected included frequency, incontinence, andnocturia data. The study data is shown in FIGS. 17A-17F. FIG. 17Aillustrates a table of subject baseline parameters, including OAB-V8score, frequency, incontinence, and nocturia rates in 24 hours. FIG. 17Billustrates a table of responder rates for nocturia, incontinence, andfrequency. FIG. 17C illustrates a table of improvement in urinaryparameters, including frequency, incontinence, and nocturia. Asillustrated in the graphs of FIGS. 17D, 17E, and 17F, urinary frequencyepisodes per 24 hours, incontinence episodes per 24 hours, and nocturiaepisodes per 24 hours generally improved with stimulation. When afeature or element is herein referred to as being “on” another featureor element, it can be directly on the other feature or element orintervening features and/or elements may also be present. In contrast,when a feature or element is referred to as being “directly on” anotherfeature or element, there are no intervening features or elementspresent. It will also be understood that, when a feature or element isreferred to as being “connected”, “attached” or “coupled” to anotherfeature or element, it can be directly connected, attached or coupled tothe other feature or element or intervening features or elements may bepresent. In contrast, when a feature or element is referred to as being“directly connected”, “directly attached” or “directly coupled” toanother feature or element, there are no intervening features orelements present. Although described or shown with respect to oneembodiment, the features and elements so described or shown can apply toother embodiments. It will also be appreciated by those of skill in theart that references to a structure or feature that is disposed“adjacent” another feature may have portions that overlap or underliethe adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Themethods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “stimulating a peripheral nerve” includes “instructingthe stimulating of a peripheral nerve.” Optional features of variousdevice and system embodiments may be included in some embodiments andnot in others. Therefore, the foregoing description is providedprimarily for exemplary purposes and should not be interpreted to limitthe scope of the invention as it is set forth in the claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A method of treating urinary symptoms in apatient with dual transcutaneous stimulation of a saphenous nerve and aposterior tibial nerve, comprising: positioning a first peripheral nerveeffector on the patient's skin to stimulate the saphenous nerve of thepatient; positioning a second peripheral nerve effector on the patient'sskin to stimulate the posterior tibial nerve of the patient; deliveringa first electrical nerve stimulation signal transcutaneously to thesaphenous nerve through the first peripheral nerve effector; deliveringa second electrical nerve stimulation signal transcutaneously to theposterior tibial nerve through the second peripheral nerve effector;receiving an input relating to autonomic nervous system activity of thepatient; and modifying at least one brain or spinal cord autonomicfeedback loop relating to bladder function based on the input to balanceparasympathetic and sympathetic nervous system activity of the patient,wherein the method does not utilize any implantable components, and onlyinvolves transcutaneous stimulation.
 2. The method of claim 1, whereinthe first peripheral nerve effector and the second peripheral nerveeffector are both positioned proximate the knee of the patient.
 3. Themethod of claim 1, wherein the first electrical stimulation signal isdifferent from the second electrical stimulation signal.
 4. The methodof claim 1, wherein the first electrical stimulation signal has a firstfrequency different from a second frequency of the second electricalstimulation signal.
 5. The method of claim 4, wherein the firstfrequency is from about 5 Hz to about 30 Hz.
 6. The method of claim 4,wherein the second frequency is from about 10 Hz to about 20 Hz.
 7. Themethod of claim 1, wherein the first electrical stimulation signal hasan amplitude different from the second electrical stimulation signal. 8.The method of claim 1, wherein receiving an input relating to autonomicnervous system activity of the patient comprises receiving data from asensor that measures autonomic nervous system activity of the patient.9. The method of claim 1, wherein receiving an input relating toautonomic nervous system activity of the patient comprises one or moreof the following features: receiving data from a sensor that measuresgalvanic skin response of the patient; receiving data relating tourinary symptoms of the patient; and receiving data relating to patientsleep state.
 10. The method of claim 1, wherein receiving an inputrelating to autonomic nervous system activity of the patient comprisesone or more of the following features: receiving data from a sensor thatmeasures a heart rate variability of the patient; receiving heart ratevariability data from an optical sensor measuring blood flowcharacteristics and disposed proximate a vessel proximate a knee of thepatient; and receiving data relating to nocturia episodes of thepatient.
 11. The method of claim 1, wherein modifying the at least onebrain or spinal cord autonomic feedback loop comprises adjusting one ormore parameters of the first electrical nerve stimulation signal. 12.The method of claim 11, wherein modifying the at least one brain orspinal cord autonomic feedback loop comprises adjusting one or moreparameters of the second electrical nerve stimulation signal independentfrom the first electrical nerve stimulation.
 13. The method of claim 1,wherein receiving an input relating to autonomic nervous system activityis done in real-time.
 14. The method of claim 1, wherein modifying atleast one brain or spinal cord autonomic feedback loop relating tobladder function is done in real-time.
 15. The method of claim 1,wherein modifying at least one brain or spinal cord autonomic feedbackloop relating to bladder function is done in a subsequent stimulationsession.
 16. The method of claim 1, wherein the balancing of sympatheticnerve and parasympathetic nerve activity comprises modulating the firstand/or second electrical nerve stimulation signals to achieve a heartrate variability within a targeted desired range.
 17. The method ofclaim 1, wherein delivering the first electrical nerve stimulationsignal and the second electrical nerve stimulation signal is below asensory threshold.
 18. The method of claim 17, further comprisingcalibrating the sensory threshold by selecting from a predetermined setof one or more parameters for at least one of the first and secondelectrical nerve stimulation signals.
 19. The method of claim 1, furthercomprising independently turning off the delivery of the firstelectrical nerve stimulation signal from turning off the secondelectrical nerve stimulation signal.
 20. The method of claim 1, furthercomprising determining parasympathetic and sympathetic nervous systemactivity of the patient prior to delivering the first and secondelectrical nerve stimulation signals so as to select one or more of astimulation waveform, a stimulator parameter, and dosing of stimulationfor at least one of the first and second electrical nerve stimulationsignals.